Method of manufacturing a wound dressing

ABSTRACT

A method of manufacturing a wound dressing having microscopic web-like interconnections and a porous structure of continuous pores throughout the wound dressing. In the first embodiment of the method, the dressing is produced by the steps of heating while simultaneously stirring a biocompatible material and solvent to form a homogenous solution; cooling while simultaneously stirring the homogenous solution to form a gel made of a dispersion of gel particles of the biocompatible material and freeze-drying the gel. In a second embodiment of the method, the wound dressing is produced by heating while simultaneously stirring a biocompatible material and the solvent to form a homogenous solution, cooling while simultaneously stirring the homogenous solution to form a gel made of a dispersion of gel particles of the biocompatible material; warming while simultaneously stirring the gel, allowing the warm gel to cool to form a soft gel and freeze-drying the soft gel. Finally, in a third embodiment of the method, the steps of heating while simultaneously stirring a biocompatible material and the solvent to form a homogenous solution, adding a liquid which inhibits the freezing of the homogenous solution, cooling while simultaneously stirring the homogenous solution to form a gel comprising a dispersion of gel particles of the biocompatible material and freeze-drying the gel.

This is a division of application Ser. No. 07/545,734 filed Jun. 29,1990.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a wound dressing, and more particularlyto a wound dressing which is suited for treatment of wounds, for exampleburns or trauma.

2. Description of the Prior Art

To date, various dressings have been developed to treat a broad range ofskin defects due to burns, trauma or wounds.

While a variety of structural contrivances have been made for such wounddressings, those being often used at present are in the form that asilicone film is adhered to one side of a fabric or sponge structure toinhibit the invasion of bacteria. This structure creates a primary vitaladhesion by absorbing the exudate from the affected site to form fibrin,and in turn enables secondary vital adhesion by ensuring the subsequentpenetration of fibroblasts and capillaries, thus resulting in the strongadhesion of the dressing to the wound surface. However, since thesilicone film allows body fluid proteins to accumulate under the film,it has a great danger of becoming a source of nourishment for bacterialgrowth present on the wound surface, so that it has the shortcoming thatthe healing of wound is disturbed.

In the sponge structure as described above, moreover, its requiredperformances such as good contacting ability with the above-mentionedexudate and blood, the efficiency of drug release, the good dressingability of affected sites, etc. have been examined less sufficiently todate. For example, the structure disclosed in the U.S. Pat. No.3,113,568 includes a barrier 20 which is made of foam having a networkstructure provided under a pad 11, as illustrated in FIGS. 12 and 13.Unit cells 21, which constitute this barrier 20, present a polyhedralstructure having each face 22 (which is three-dimensionally linked byleg-like links 23 to become pores) formed. Therefore, this structure issimply network-like, not structurally satisfying each of theabove-mentioned required performances to a sufficient extent. In otherwords, since the network-like structure is only linked by the leg-likelinks 23, it involves the following problems: the contact area havingcontact with exudate and blood is not sufficient; the mechanicalstrength of the network object is low; the drug dispersed from thenetwork-like structure (which is contained in the structure beforehand)is released less efficiently; and the barrier effect on bacteria stillremains to be improved. These problems are found generally in otherknown sponge structures.

OBJECTS AND SUMMARY OF THE INVENTION

Continuing various studies on wound dressings including the conventionaltherapeutic dressings for skin defects, the present inventor hassucceeded in specifically modifying the porous structure of a spongestructure, thus reaching the present invention.

The first object of the present invention is to provide a wounddressing, which can enlarge the contact area between exudate or bloodand the material promote coagulation and incrustation, increase themechanical strength, disperse the drug on the surface of the material toraise the efficiency of its release, enhance the barrier efficiencywithout reducing the permeability of moisture and vapor, and obtain ahigher dressing effect at the state of incrustation.

The second object of the present invention is to provide a method bywhich the wound dressing can be manufactured reproducibly, bothefficiently and well.

That is to say, the present invention relates to a wound dressing,wherein a porous structure having many pores is formed by athree-dimensional structure composed of a combination of minutefilm-like links, i.e., filmy interconnections, in a wound dressing ofthe porous structure.

In addition, the method of manufacturing in accordance with the presentinvention is divided into the following three types:

The first manufacturing method is a method of manufacturing a wounddressing which has the following steps: warming with stirring abiocompatible or base material-containing solution to produce ahomogeneous solution; cooling with stirring this homogeneous solution tocreate a dispersion gel in which the base material-containing gelparticles are dispersed; and freeze-drying this dispersion gel.

The second manufacturing method is a method of manufacturing a wounddressing which has the following steps: warming with stirring a basematerial-containing solution to produce a homogeneous solution; coolingwith stirring this homogeneous solution to create a dispersion gel inwhich the base material-containing gel particles are dispersed; warmingwith stirring this dispersion gel; and freeze-drying this warm gel afterit is allowed to cool.

The third manufacturing method is a method of manufacturing a wounddressing which has the following steps: warming with stirring a basematerial-containing solution to produce a homogeneous solution; coolingwith stirring this homogeneous solution to create a dispersion gel inwhich the base material-containing gel particles are dispersed; andfreeze-drying the dispersion gel under the presence of a liquid whichinhibits the freezing of the dispersion gel which controls the freezingof this dispersion gel.

Other objects, features and advantages of the invention will appear morefully from the following detailed description thereof taken inconnection with the accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1 to 11 illustrate the embodiments of the present invention,wherein:

FIG. 1A is a scanning electron micrograph of a part of the filmstructure of the surface of a Type 1 wound dressing;

FIG. 1B is a similar scanning electron micrograph of the internalportion of the Type 1 wound dressing;

FIG. 1C is a similar scanning electron micrograph of the wound surfaceside of the Type 1 wound dressing;

FIG. 1D is a scanning electron micrograph of the film structure of thecross section of the wound dressing;

FIG. 2A is a scanning electron micrograph of the film structure of apart of the surface of a Type 2 wound dressing;

FIG. 2B is a similar scanning electron micrograph of the internalportion of the Type 2 wound dressing;

FIG. 2C is a similar scanning electron micrograph of the wound surfaceside of the Type 2 wound dressing;

FIG. 2D is a scanning electron micrograph of the film structure of thecross section of the Type 2 dressing;

FIG. 3A is a similar scanning electron micrograph of the film structureof a part of the surface of a Type 3 wound dressing;

FIG. 3B is a similar scanning electron micrograph of the internalportion of the Type 3 dressing;

FIG. 3C is a similar scanning electron micrograph of the wound surfaceside of the Type 3 wound dressing;

FIG. 3D is a scanning electron micrograph of the film structure of thecross section of the Type 3 wound dressings;

FIG. 4 is a sectional perspective view of a wound dressing;

FIG. 5 is a sectional view showing a state of pouring dispersion gelinto a mold;

FIG. 6 is a schematic view showing the freezing state of dispersion gelused for manufacturing a Type 1 wound dressing;

FIG. 7 is a schematic view showing the state of dispersion gel used formanufacturing a Type 2 wound dressing;

FIG. 8 is a sectional view showing a cup used for a vapor permeabilitytest;

FIG. 8A is a graph showing test results of a vapor permeability test fora wound dressing according to the present invention and a prior artwound dressing;

FIG. 9 is a sectional view and a graph showing a device used for a serumpermeability test and the test results;

FIG. 9A is a graph showing the test results of a serum permeability testfor a wound dressing according to the present invention.

FIG. 10 is a graph showing the results of a plasma permeability test;

FIGS. 11(A), (B), (C), (D), and (E) are respective plane views of a partof a wound dressing having various perforations;

FIG. 12 is a sectional view of a conventional wound dressing; and

FIG. 13 is an enlarged perspective view of the network structural unitof a conventional wound dressing.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

Wound dressings in accordance with the embodiments described belowinclude, for example, the following three types (Type 1, Type 2 and Type3):

Type 1

A type obtained by freeze-drying a polyamino acid dispersion gel.

Type 2

A type obtained by warming and then freeze-drying a polyamino aciddispersion gel.

Type 3

A type obtained by freeze-drying a polyamino acid dispersion gelcontaining cyclohexane.

While the manufacturing methods of these types will be described later,the structure of each type of wound dressing obtained is shown in FIGS.1 to 3, respectively. In the description below, however, the respectiveregions of the surface, internal portion, and wound surface side of thewound dressing are as shown in the drawings. But usually, the surfacerepresents a surface area having a depth of 10 to 200 μm from theoutermost part, the wound surface side means an opposing surface areaalso having a depth of 10 to 200 μm from its outermost part, and theinternal portion signifies a region between the surface and the woundsurface side. FIG. 4 illustrates a section of a wound dressing in whicha core or reinforcing material composed of nylon mesh 3 is embedded,causing the texture of the dressing to have changed with this corematerial as a border.

FIGS. 1A, 1B and 1C are the scanning electron micrographs of the filmstructure of a part each of the surface, internal portion and woundsurface side of a Type 1 wound dressing. It can be seen from thesemicrographs that a Type 1 wound dressing has an unique porous structurewhich is so constituted as to contain pores 2 through three-dimensionallinkage of minute film-like links (or film pieces). This is completelydifferent from the porous structure which is constituted by leg-likelinks as shown in FIG. 13. To be specific, the film-like links areproduced in correspondence With dispersed particles in the dispersiongel as will be described later, possessing a relatively large width, andlink between pores 2 in a continuous way (as continuous pores) withoutbeing isolated. The pores 2 themselves are large in size and numerous aswell. Many of these pores are found especially in the internal portionof the wound dressing, but there are also numerous pores in the woundsurface side, and a relatively tight surface layer is formed on thesurface (see FIG. 1D showing a scanning electron micrograph of the filmstructure of the cross section.)

According to the Type 1 structure, the following marked effects, whichhave not been available to date, can be obtained.

(1) Since many pores 2 (which have a substantially uniform pore diameterin each region) are embedded in the three-dimensional structure formedby the film-like links 1, the contact area between exudate or blood fromthe wound surface and the material is enlarged, so that coagulation andincrustation can be promoted, and mechanical strength can be increased.

(2) In addition, the release efficiency of a drug (which can becontained in the material beforehand, as will be described later)present in the dispersion on the surface of the biocompatible materialcan be increased.

(3) The barrier effect of the wound dressing can be raised withoutreducing its moisture and vapor permeability, and a more effectivedressing can be obtained at the stage of incrustation.

FIGS. 2A, 2B, and 2C are the scanning electron micrographs of the filmstructure of a part of each of the surface, internal portion and woundsurface side of a Type 2 wound dressing, and FIG. 2D is a scanningelectron micrograph of the cross section of the wound dressing. Thesemicrographs reveal that a Type 2 wound dressing, like a Type 1, has anunique porous structure which is so constituted as to contain pores 2through the three-dimensional linkage of minute film-like objects 1. Andthe structure of this Type 2 dressing is characterized by a greaterwidth of the film-like links 1 and a larger diameter of pores 2,compared to a Type 1 dressing. This is thought to be due to thefreeze-drying of the dispersion gel after warming, as shown in themanufacturing method which will be described later, which has alreadychanged into an intermediate state of gel between dispersion andnon-dispersion gel (i.e., a homogeneous gel consisting of a uniformphase with no dispersed particles) before freezing. A Type 2 dressingexhibits the properties as a Type 1 dressing, as well as having a betterstrength of the dressing than a Type 1.

FIGS. 3A, 3B, and 3C show the scanning electron micrographs of the filmstructure of a part of each of the surface, internal portion and woundsurface of a Type 3 wound dressing, and FIG. 3D shows a scanningelectron micrograph of the film structure of the cross section of thewound dressing. These micrographs show that the Type 3 wound dressing,like Type 1, has a unique porous structure which is so constituted as tocontain pores 2 through the three-dimensional linkage of minutefilm-like links 1. And it seems that in the structure of this Type 3dressing, the film-like links 1 are linked in a more complicatedfashion, compared to the Types 1 and 2 dressings. This is thought to bedue to the presence of cyclohexane, as shown in the manufacturing methodthat will be described later, which has made it difficult for thedispersion gel to be frozen. The Type 3 dressing has the same propertiesas the Type 1 dressing, as well as the merits of both the Types 1 and 2,and is satisfactory not only in its moisture permeability andtransduction but also in its strength.

According to the dressings shown in FIGS. 1D, 2D, and 3D, respectively,nylon mesh 3 of a fibrous thickness ranging from 1 to 50 denier and anumber of fibers per inch ranging from 1 to 100, is included. Forexample, mesh having a thickness of 15 denier and a division number of40 per inch is embedded in the wound dressing. The biocompatiblematerial is then entangled with this mesh, thus leading to improvedstrength. And it is seen that with the mesh 3 as a border, the filmtexture is relatively tight on wound surface 3I, having large pores 2 onsurface side 32 and small pores 2 on wound surface 31. When a dispersiongel 7 is poured into a mold 8 placed on a plate 42 as shown in FIG. 5,the mesh 3 serves as a filter to allow fine particles to pass throughthe mesh 3 to the wound surface side especially when the gelconcentration is not lower than 0.2%, whereas coarse particles tend toremain closer to the surface side of the mesh 3 without passing through.As a result, as described above, the textures of both sides are variedwith the mesh 3 as the border. Since the wound surface side has thepores 2 which are smaller, but more than the opposing surface of themesh 3, its moisture permeability and strength, as well as drug release,are all satisfactory; and since the surface side of the mesh 3 has thepores 2 which are larger, its moisture permeability becomes stillbetter, and its strength is also satisfactory due to the film-like links1 having a large width and reinforcement effect added by the mesh 3,coupled with good pliability and cushiony properties. In addition, thetexture of surface 32 is relatively tight, improving the effect ofpreventing the invasion of bacterial from outside. Such relativetightness of the surface 32 is estimated to be due to the followingreason: as schematically illustrated in FIG. 6, a temperature gradientshowing a gradual increase in temperature from the side of the plate 42towards the surface is formed upon freezing, and crystallites 33 of asolvent (such as benzene) are produced between dispersed particles 4from the side of the wound surface, so that the polyamino acid is pushedtowards the surface, resulting in an increase in the density.

FIG. 4 is a sectional perspective view (in which a virtual line 40represents a living body) of the wound dressing 41 in accordance withthis embodiment.

This wound dressing 41 is a film-like object, the whole of which iscomposed of highly biocompatible or tissue-compatible porouspoly-α-amino acid and contains, for example, sulfadiazine silver as anantimicrobial agent. The dressing may have a thickness of 0.1 to 10 mm,for example, 1 mm, and a thin surface layer 32 having a thickness of 0.5to 5 μm, especially 1 to 3 μm formed on the surface. The pore diameterof a pore 2 in the surface layer 32 may be 20 μm or less, and the porediameter of a pore 2 in interior 30 may range from 20 to 500 μm. Areinforcing material composed of, for example, nylon mesh 3, embedded inthe internal portion 30, increases the strength of the wound dressing 41to prevent if from being torn during usage. This wound dressing 41 isalso provided with many minute perforations 10 which pass through thedressing. The diameter of the minute perforations ranges from tens toseveral thousands μm, and their pitch d may be 10 mm.

Accordingly, body fluid discharged from the wound surface of the livingbody 40 passes through many pores 2 and infiltrates from the woundsurface side 31 of the wound dressing 41 into the internal portion 30,as well as exudes by capillarity to the opposing surface layer 32through the minute perforations 10. Thus, body fluid is effectivelyabsorbed into the wound dressing 41 without remaining at the boundarybetween the wound surface of the living body 40 and the wound dressing41. Accordingly, the danger of bacterial growth due to the retention ofbody fluid is prevented, leading to enhancement of the wound healing.The pores in the surface layer 32 are fine as described above,preventing bacterial invasion from the outside.

The antimicrobial agent in the wound dressing 41 can destroy bacteria onthe wound surface and thereafter inhibit infections due to bacterialinvasion from the outside. This requires the antimicrobial agent to bepreferably released in trace amounts at a certain rate. In this case,the above-mentioned base material of the porous layer particularly iscomposed of hydrophobic poly-α-amino acid, thereby markedly limiting thecirculation of fluid in the layer and enabling the agent to be releaseover a prolonged period.

In this example, in addition, it is possible to allow the antimicrobialagent to be contained in the porous layer and develop its time-releaseeffect. For this purpose, the content of the antimicrobial agent may be0 to 100 parts by weight or 0 to 50 wt % (compared to 100 parts for thebase polymer).

Highly biocompatible or tissue-compatible poly-α-amino acids used inthis example include poly (γ-benzyl-L-glutamate) (PBLG),poly(L-leucine), poly(N.sup.ε -carbobenzoxy-L-lysine), and thecombinations of these amino acids. These poly-α-amino acids are filmmaterials having superb workability in particular since they arehydrophobic, readily polymerized, and soluble in benzene or dioxane,which can be removed by freeze-drying.

Moreover, local antimicrobial agents useable in this example includesulfadiazine silver, sulfadiazine zinc, sulfadiazine cerium, silvernitrate, and gentamicin. These antimicrobial agents are added to theabove-mentioned highly histotropic porous film materials, and wounddressings can be produced with the resulting mixtures.

Furthermore, other agents such as vasoconstrictors (for hemostasis) andanalgesics can be advantageously contained in the porous layer, incombined use with the above-mentioned antimicrobial agents.

In the wound dressing in accordance with this example, the core material3 embedded in the porous layer (that is, lying in between) plays therole of giving mechanical strength to the dressing. Such a dressing candress and protect the wound surface for a given treatment period asrequired, for example, for deep dermal burn and deep burn. The porouslayer can then detach from the core material. Upon such detachment, thebiocompatible base material remaining in the tissues reproduced isdecomposed and absorbed in the living body. In this sense, particularly,unless the internal porous layer has some thickness (0.1 to 10 mm), asdescribed above, the portion adhering to the body tissue would bedetached. Further, the efficiency of removing the dressing aftertreatment can be improved by controlling the position at which the corematerial is embedded.

Applying the dressing to the wound surface leads to incrustation joinedby exudate and blood. If the nylon mesh 3 is present in the dressing,the whole dressing can be removed by detaching the nylon mesh 3. Thismakes it necessary to properly control the position at which the nylonmesh should be incorporated.

The wound dressing in accordance with this example, when used with itsattachment to the living body, preferably has sufficient flexibility tobend in correspondence with any movement of the living body. Otherwise,it would be readily detached from the living body if it has noflexibility. To provide the dressing with such flexibility, it ispreferable that the above-mentioned core material 3 has properflexibility (or elasticity). Such core materials 3 include naturalfibers (such as protein fiber, cellulose fiber, and mineral fiber),synthetic fibers (made of, for example, polyurethane, polyolefin,polyvinyl chloride, polyvinylidene chloride, polyamide, silicone, andpolyester) and metallic fibers (made of, for example, stainless steeland copper). The core material is desirably in the form of mesh, and canbe produced in nylon mesh or silicone gauze.

It is desirable that substance having good affinity for the living body(or enhancing the wound healing) is allowed to adhere to at least oneside (especially the wound surface side) of the wound dressing inaccordance with this example. A wound dressing laminated with a layer ofsuch a substance can promote initial vital adherence and inhibitretention of the exudate between the dressing and the wound surface,thus accelerating the treatment. In the process of lamination, a porouslayer of the above-mentioned substance is provided, and a dressing isthen formed on this layer by the above-described method, or a solutionof the substance is applied to the surface of the dressing, followed byfreeze-drying. The above-mentioned substances include such serumproteins as fibrinogen, albumin, γ-globulin and fibronectin, collagens(including atherocollagen), gelatin, and mucopolysaccharides.

Among these, fibrinogen is a blood coagulating protein and forms fibrinby the action of thrombin. Since fibrin exhibits superb adhesion andproliferative properties towards fibroblasts, application of fibrinogento the wound surface side of the dressing causes the development of itshemostatic effect and, at the same time, reveals its good vital adhesionand therapeutic effect for the wound. In addition, since collagen is amaterial exhibiting excellent adhesive and proliferative propertiestowards fibroblasts, the dressing likewise exhibits vital adhesion andtherapeutic effect for the wound.

Next, the process of manufacturing each type of wound dressing describedabove will be explained.

First, a mold 8 having the size of about 52 cm×14 cm, as shown in FIG.5, is used, and nylon mesh 3 having a weight of about 0.26 g per cm² isextended at the level of 5 mm above the bottom surface of the mold. Inpreparing dispersion gel 7 (polyamino acid dispersion gel) to be pouredinto the mold 8, the following mixture is prepared to yield, forexample, the concentration of poly(L-leucine) of 0.11 w/v %. Thepreparation is performed normally at a poly(L-leucine) concentrationranging from 0.01 to 1 w/v %.

    ______________________________________                                        Benzene         10 lit. (1 batch)                                             Poly(L-leucine) 11 g                                                          Sulfadiazine silver                                                                            4 g                                                          ______________________________________                                    

While being stirred, this mixture is warmed to no less than 55° C., atemperature at which the solution undergoes no change in structure,especially to 70° C. to 75° C., with benzene not evaporated, and auniform solution is obtained for over three hours. When converted to thevolume of the above-mentioned mold 8, the composition of thishomogeneous solution is as follows:

    ______________________________________                                        Benzene      728 ml (poured a 10 mm thickness)                                Poly(L-leucine)                                                                            0.8008 g                                                         Sulfadiazine silver                                                                        0.2912 g                                                         ______________________________________                                    

Benzene is preferred as the solvent, but another solvent of polyleucinecan be used.

Production of Type 1

The homogeneous solution prepared above is cooled with stirring to atemperature range from no more than 55° C. to approximately roomtemperature, thereby leading to formation of the dispersion gel havingdispersed particles with a particle size of 10 to 1000 μm containingpoly(L-leucine), benzene, and sulfadiazine silver. Furthermore, aftersaid homogeneous solution is cooled to room temperature as a homogeneousgel, the dispersion gel can be prepared by performing the operation ofmashing or filtering the homogeneous gel. Nonetheless, it is moreefficient to prepare the homogeneous solution by cooling it withstirring as described above. The dispersion gel obtained is composed ofthe gel particles dispersed in a dispersion liquid (which is very slightin amount). Next, this dispersion gel is, as shown in FIG. 5, pouredinto the mold 8 at room temperature, and is then freeze-dried. Thefreezing temperature is set a 0° C. to -40° C. (e.g., -10° C.), and thesubsequent drying is performed at 0° C. to 80° C. for example, 10° C.(the temperature of the plate 42) with the benzene being evaporatedunder reduced pressure. The state upon freezing is thought to be asfollows: as schematically illustrated in FIG. 6, freezing progressesfrom the region near the plate 42 (wound surface); free benzene 33between dispersed particles 4 is promptly crystallized; and thecrystallization then occurs gradually from the bottom towards the top,thus followed by the formation of a fibrous structure in the woundsurface side 31, a network structure in the internal portion (internallayer) 30, and a relatively tight structure in the surface 32,respectively, during the above-mentioned course. The dispersionparticles 4 correspond to the portion constituting the already describedfilm-like matter 1, with many pores formed at the space where benzenehas been evaporated.

Minute perforations 10 with 1 mm φ or 2 mm φ are formed in zigzags atintervals of 10 mm in porous film with the above-obtained nylon meshbuilt in, and a wound dressing of Type 1 is thus produced.

Production of Type 2

The dispersion gel prepared above is warmed with stirring at 56° C. fornor more than 10 minutes (e.g., 7.5 min.) or at 52° C. for 1 to 3 hours,thereby resulting in the preparation of gel in an intermediate statebetween the above-mentioned dispersion gel and homogeneous gel. This gelis, as shown in FIG. 5, poured into the mold with the stirringtemperature maintained. It is then allowed to cool to form a soft gel.

This is freeze-dried in the same manner as described above, followed bythe formation of minute perforations to produce a wound dressing of Type2. In case of this Type 2 dressing, since the dispersion gel is warmedand poured into the mold as described above, it is thought that warminghas allowed the interaction of the dispersed particles 4 prior tofreezing as schematically illustrated in FIG. 7, causing the productionof the gel in the intermediate state and thus resulting in the formationof a unique structure as shown in FIG. 2.

Production of Type 3

This type of wound dressing can be produced by the following twomanufacturing methods, depending upon the time when cyclohexane isadded:

(a) Added upon dissolution:

When the above-described homogeneous solution is prepared, cyclohexaneis added in an amount of 0.1% to 20%, preferably 0.5% to 10%, forexample 1%, compared to the benzene, and is stirred at 70° C. to 75° C.for about one hour; then, it is cooled with stirring to a range from 55°C. to approximately room temperature, thus resulting in preparation ofthe dispersion gel. This dispersion gel is poured into the mold at roomtemperature in the same manner as described above and, afterfreeze-drying, a wound dressing of Type 3 is produced with minuteperforations formed.

(b) Added after dispersion:

Cyclohexane is added to the dispersion gel used for Type 1 in an amountof 0.1% to 20%, preferably 0.5% to 10%, for example, 1%, compared to thebenzene, and this dispersion gel is poured into the mold at roomtemperature in the same manner as described above and, afterfreeze-drying, a wound dressing Type 3 is produced with minuteperforations formed.

Since both wound dressings of (a) and (b) above are freeze-dried withthe cyclohexane present (or is added) the cyclohexane makes it difficultfor the gel as a whole to be frozen and brings it into an supercooledstate. Thus, it is thought that this makes the process of freezingdifferent from those of Type 1 and Type 2 and thus leads to the creationof a unique structure as shown in FIG. 3. Nonetheless, the cyclohexaneis evaporated upon drying and does not remain in the film.

Cyclohexane is believed to control the freezing process in this manner,but substances other than cyclohexane having no great differences inmelting and boiling points from benzene can be used as an additivesubstance which exhibits the same effects as cyclohexane: for example,dioxane and cyclooctane. As for the amount of addition, 0.1% to 20%compared to the benzene, is appropriate, for example, 1% to 2% isdesirable. If the amount is too low, then there is no additive effect,and if it is too high, the film structure obtained becomes defective.

The following tests were performed with each of the wound dressings asproduced above.

(1) Tensile strength

The measurements of tensile strength along the extension of nylon meshare as follows:

Type 1: 0.69 kg/cm²

Type 2: 1.02 kg/cm²

Both types exhibited a strength of 0.5 kg/cm² or more, proving that theywere satisfactory in terms of strength.

(2) Vapor permeability

Using a cup 52, as shown in FIG. 8, a wound dressing 41 (the vaporpermeating portion of which is a circle with a diameter of 6 cm) isextended, and with a ring-shape portion 50 tightened and sealed byparaffin 51. Water passing through the wound dressing 41 as permeatingmoisture was determined from an increase in the weight of a drying agent53 under the atmosphere of 40° C. and 75% RH. The results are presentedin FIG. 8

It can be seen from these results that each of Type 1, 2, and 3 wounddressings have high moisture permeability. The uniform gel freeze-driedproduct shown in FIG. 8 represents a wound dressing made byfreeze-drying the above-mentioned uniform gel as it was.

(3) Serum permeability

A millipore filter holder 63, which places a wound dressing 41 at thelower end of a pipe 62 to convey equine serum 60 from a transfusionbottle 61 containing the equine serum, was provided as shown in FIG. 9,and the flow rate of the serum dropping into a collection bottle 64 wasmeasured while changing the height H. The results are illustrated inFIG. 9.

These results reveal that the serum permeability of Type 1, 2, and 3wound dressings (especially Type 3) is satisfactory.

(4) Plasma permeability

For this purpose as well, with equine plasma collected in place of theequine serum 60 using the device in FIG. 9, the flow rate of it wasmeasured in the same manner. FIG. 10 show the results.

These results also reveal that the plasma permeability of Types 2 and 3(no test conducted with Type 3) is good.

(5) Animal experiment

Using a rabbit with a weight of about 3 kg, its dorsal region was shavedoff and disinfected under general anesthesia with sodium pentobarbital,and a split-thickness skin defect having a depth of 20/1000 inch and asize of 25×50 mm was created with an electric dermatome. The woundsurface was covered with each wound dressing, on which sterilized gauzeand sterilized cut cotton were in turn placed, and was then pressed andfixed with elastic bandage. On the tenth post-operative day, the woundsite was macroscopically observed, and the section of the wound was thenhistologically observed by hematoxylin and eosin stain. When the samplesof Type 1, 2 and 3, wound dressings, respectively, were used, themacroscopic observations revealed the completion of epithelialization ineach of them. In the histological observations, these samples presentedthe penetration of exudate into the wound dressings, as well as healthygraduation and epithelialization on the wound surface. Comparativeexamples such as BIOBRANE®-type biosynthetic skin consisting of knittednylon fabric bonded to an ultrathin silicone membrane by U.S. WoodroofLaboratories Inc. and OPSITE®-type adhesive backed polyurethane dressingby U.K. Smith and Nephew Medical Limited, i.e., commercially availablewound dressings, were tested in the same manner. As a result,macroscopic observations showed little epithelialization in either ofthese dressings, and in histological observations, no permeation ofexudate into the wound dressings was revealed in either, coupled withlittle healing confirmed on the wound surface.

It will be evident that various modifications can be made to thedescribed embodiments without departing from the scope of the presentinvention.

For example, the film structure or texture of a wound dressing inaccordance with the present invention can be modified in various waysdepending upon the size and distribution of the above-describedfilm-like objects, the size and distribution of pores, etc. In addition,the material, composition and other aspects of the dressing are notrequired to be limited to those stated above. The type and amount of asolvent to be used and the location of nylon mesh may be altered, andcore material may be formed with a material other than nylon mesh.Further, the nylon mesh can be omitted.

As shown in FIG. 11, in addition, minute perforations 10 to be formed ina wound dressing can also be varied into small round shape (FIG. 11(A)), slit-like cut 10' penetrating from surface to back as in FIG. 11(B), cross-shaped cut 10' penetrating from surface to back as in FIG. 11(C), X-shaped cut 10' penetrating from surface to back as in FIG. 11(D), and tiny pinhole-shaped through-holes 10' as in FIG. 11 (E). Thoseminute perforations shown in FIG. 11 (B) to (E) produce no cut-offresidue when cuts or holes are formed, and in those shown in FIG. 11 (C)and (D) the state of the wound surface inside the dressing can bevisually examined when the intersection of cross or X letter is turnedup with fingers.

In regard to the above described manufacturing methods, moreover, theabove-mentioned time of cyclohexane addition may be altered in themanufacturing process of, for example, a Type 3 dressing and, asoccasion demands, for example, it may be added upon preparation of thehomogeneous gel or dispersion gel, respectively.

In accordance with the present invention, as described above, sincepores are contained in a three-dimensional structure made by minutefilm-like links, the contact area between the exudate and blood from thewound surface and the material is enlarged, thus enabling theacceleration of coagulation and incrustation, as well as increasing themechanic strength. Moreover, the release efficiency of any drug presentin dispersion on the surface of the material can be raised, and thebarrier effect can be increased without reducing the permeability ofmoisture and vapor, so that higher dressing effect can be obtained atthe stage that crust has been formed.

What is claimed is:
 1. A method of manufacturing a wound dressing havingmicroscopic web-like interconnections and a porous structure ofcontinuous pores throughout the wound dressing, comprising the stepsof:heating while simultaneously stirring poly-α-amino acid and a solventto form a homogeneous solution; cooling while simultaneously stirringthe homogeneous solution to form a gel comprising a dispersion of gelparticles of the poly-60 -amino acid; and freeze-drying the gel.
 2. Amethod of manufacturing as defined in claim 1, whereinthe gel particlesof the poly-α-amino acid have a size of about 10 to 1000 μm; the step ofheating while simultaneously stirring is at a sufficiently lowtemperature that the solution undergoes no structural change and thesolvent is not evaporated; and the step of freeze-drying furthercomprises freezing the gel at a temperature of about -40° C. to 0° C.and evaporating the solvent under reduced pressure at a temperature ofabout 0 to 80° C.
 3. A method of manufacturing a wound dressing havingmicroscopic web-like interconnections and a porous structure ofcontinuous pores throughout the wound dressing, comprising the stepsof:heating while simultaneously stirring a poly-α-amino acid and asolvent to form a homogeneous solution; cooling while simultaneouslystirring the homogeneous solution to form a gel comprising a dispersionof gel particles of the poly-α-amino acid; warming while simultaneouslystirring the gel; allowing the warmed gel to cool to form a soft gel;and freeze-drying the soft gel.
 4. A method of manufacturing as definedin claim 3, whereinthe gel particles of the poly-α-amino acid have asize of about 10 to 1000 μm; the step of heating while simultaneouslystirring is at a sufficiently low temperature that the solutionundergoes no structural change and the solvent is not evaporated; thestep of allowing the warmed gel to cool comprises pouring the warmed gelinto a mold and allowing the warmed gel to cool; and the step offreeze-drying further comprises freezing the gel at a temperature ofabout -40° C. to 0° C. and evaporating the solvent under reducedpressure at a temperature of about 0° C. to 80° C.
 5. A method ofmanufacturing a wound dressing having microscopic filmy interconnectionsand a porous structure of continuous pores throughout the wounddressing, comprising the steps of:a) heating while simultaneouslystirring a poly-α-amino acid and a solvent to form a homogeneoussolution; b) adding a liquid which inhibits the freezing of thehomogeneous solution; c) cooling while simultaneously stirring thehomogeneous solution to form a gel comprising a dispersion of gelparticles of the poly-α-amino acid; and d) freeze-drying the gel.
 6. Amethod of manufacturing a wound dressing as defined in claim 5, whereinsteps (a) and (b) are concurrent, and the liquid which inhibits thefreezing of the homogeneous solution is in the amount of 0.1 to 20% byweight of the solvent.
 7. A method of manufacturing a wound dressing asdefined in claim 5, wherein step (b) is performed immediately after step(c), and the liquid which inhibits the freezing of the homogeneoussolution is in the amount of 0.1 to 20% by weight of the solvent.
 8. Amethod of manufacturing as defined in claim 5, whereinthe gel particlesof the poly-α-amino acid have a size of about 10 to 1000 μm; the step ofheating while simultaneously stirring is at a sufficiently lowtemperature that the solution undergoes no structural change and thesolvent is not evaporated; and step (b) is performed immediately afterstep (c); further comprising, prior to step (d), the step of pouring thegel into a mold, and the step of freeze drying further comprises freeingthe gel at a temperature of about -40° C. to 0° C. and evaporating thesolvent under reduced pressure at a temperature of about 0° C. to 80° C.9. A manufacturing method as in claim 5, wherein said liquid whichinhibits the freezing of the homogeneous solution has a melting pointwithin 6° C. and a boiling point within 21° C. to that of said solvent.